Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: T cell reconstitution after lymphoablation in allograft recipients may lead to acute rejection and poor graft outcome. Using a mouse model of heart transplantation and murine anti-thymocyte globulin (mATG) we showed that while T cell recovery depends on B cells, B cell MHC expression is dispensable. The goal of this study was to investigate the role of B cell derived IL-1β and IL-6 in T cell homeostatic reconstitution after mATG lymphoablation.
*Methods: B6 (H-2b) recipients of BALB/c (H-2d) heart allografts were treated with mATG (d. 0, 4). The NanoString gene expression analysis showed that mATG upregulated IL-1β and IL-6 expression in recipient B cells. To validate NanoString findings, IL-1β and IL-6 expression was measured by intracellular flow cytometry. To test the role of IL-6 and IL-1β during T cell recovery, we treated recipients with mATG plus neutralizing anti-IL-1β mAb or anti-IL-6 mAb or used IL-1R1, caspase-1, MyD88 or IL-6 KO recipients. To test the requirement for B cell derived IL-1β or IL-6, caspase-1 KO or IL-6 KO B cells were adoptively transferred into B cell deficient μMT heart allograft recipients treated with mATG. The possibility of IL-1β or IL-6 direct effect on T lymphocytes was assessed by adoptive co-transfer of WT and either IL-1R or IL-6R KO T cells into heart allograft recipients and comparing their reconstitution after mATG treatment.
*Results: Following heart allograft placement and mATG treatment, B cells are the main source of IL-1β and IL-6, and these cytokines mutually regulate each other’s production. Either treatment with anti-IL-1β mAb or the use of IL-1R1 KO, caspase-1 KO and MyD88 KO recipients diminished both CD4+ and CD8+ T cell recovery along with improved heart allograft survival and decreased donor-reactive IFN-γ producing cells after mATG treatment. Similarly, in vivo IL-6 neutralization with mAb or using IL-6 KO recipients delayed CD4+ and CD8+ T cell recovery, markedly prolong heart allograft survival and decreased donor specific T cell responses. Adoptive B cell transfers into μMT mice showed that B cell derived IL-1β and IL-6 supported CD8+ T cells homeostatic proliferation. The absence of either IL-1R or IL-6R on CD8+ T cells markedly impaired their homeostatic recovery following mATG depletion.
*Conclusions: These findings reveal the essential role of B cell-derived IL-1β and IL-6 during homeostatic T cell expansion in a clinically relevant model of lymphoablation.
To cite this abstract in AMA style:Hasgur S, Fan R, Valujskikh A. B Cell Derived IL-1β and IL-6 Drive Homeostatic T Cell Recovery Following Lymphoablation [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/b-cell-derived-il-1%ce%b2-and-il-6-drive-homeostatic-t-cell-recovery-following-lymphoablation/. Accessed March 6, 2021.
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